1. Alpha/Beta Structures Branden & Tooze, Chapter 4

2. Alpha / Beta Structures The most regular and common domain structures consist of repeating beta-alpha-beta super-secondary units –A central core of parallel beta sheets surrounded by outer layer of alpha helices. These folds are called alpha/beta, or wound alpha beta. There are three main classes of  proteins (built from  folds): –TIM barrel –Rossman Fold (open sheets) –Horseshoe fold

3. TIM Barrel Triose-phosphate isomerase (TPI or TIM) catalyzes isomerization of dihydroxyacetone phosphate and D- glyceraldehyde 3-phosphate during glycolysis. Structurally, TIM consists of a core of twisted parallel  strands arranged surrounded by  helices (sequential   motifs). Function as a dimer (2 connected sub- units). In humans, TPI deficiencies associated with a progressive, severe neurological disorder called triose phosphate isomerase deficiency, characterized by chronic hemolytic anemia. Usually associated with mutation of E at position 104 to D. Triosephosphate isomerase Orosz, F.; Oláh, J. (2008). "Triosephosphate isomerase deficiency: facts and doubts". IUBMB Life 58 (12): 703–715

4. Properties of TIM Barrel In most  -barrel structures the eight  strands of the barrel enclose a tightly packed hydrophobic core formed entirely by side chains from the  strands. The core is arranged in three layers, with each layer containing four side chains from alternate  strands. The schematic diagram shows this packing arrangement in the  barrel of the enzyme glycolate oxidase.   -barrel has been found in more than 15 proteins.  Most are enzymes with completely different AA sequences and functions.  Branched hydrophobic side chains form the core within these proteins.

5. Methylmalonyl-coenzyme A Mutase One exception, the inside of the barrel methylmalonyl-coenzyme A mutase is lined by small hydrophilic side chains (serine and threonine) from the  strands, which creates a hole in the middle where one of the substrate molecules, coenzyme A (green), binds along the axis of the barrel from one end to the other. Deficiency of this enzyme can cause Methylmalonic acidemia, which can lead to encephalopathy and death, if untreated.

6.  Barrel Active Site The active site in all a/b barrels is a pocket formed by the flexible loop regions that connect the carboxy ends of the b strands with the adjacent a helices (a). A view from the top of the barrel of the active site of the enzyme RuBisCo (ribulose bisphosphate carboxylase), which is involved in CO 2 fixation in plants and requires binding of Mg 2+ in the active site.

7. Alpha / Beta Structures Open  Sheet Open twisted  -sheets are surrounded by  -helices on both sides of the  -sheets. From the topology shown, a loop-helix-loop sequence creates a separation, or crevice, between  -strands, which is the active site. 2 examples of different types of open twisted  structures (a) the FMN(flavin mononucleotide)-binding redox protein Flavodoxin and (b) the enzyme adenylate kinase, which catalyzes the reaction AMP + ATP ↔ 2 ADP.

8. Active Site of Open  Sheet There are always two adjacent  - strands on opposite sides of a  - sheet. One of the loops from one of these two  -strands goes above the  -sheet, whereas the other loop goes below, which creates a crevice outside the edge of the  -sheet between two loops. Almost all binding sites in this class of proteins are located in crevices at the carboxy end of the  sheet. A schematic view of the active site of tyrosyl-tRNA synthetase. Tyrosyl adenylate, the product of the first reaction catalyzed by the enzyme, is bound to two loop regions: residues 38 - 47, which form the loop after  strand 2, and residues 190 - 193, which form the loop after  strand 5. The tyrosine and adenylate moieties are bound on opposite sides of the  sheet outside the carboxy ends of  strands 2 and 5.

9.  –horseshoe Fold  –horseshoe Fold is formed by amino acid sequences that contain repetitive regions of a specific pattern of  helices and  -strands. The  strands form a curved parallel  sheet with all the  helices on the outside. Schematic diagram of the structure of the ribonuclease inhibitor. The molecule, which is built up by repetitive  loop-  motifs, resembles a horseshoe with a 17-stranded parallel  sheet on the inside and 16  helices on the outside.

10. Leucine-rich Motifs Consensus amino acid sequence and secondary structure of the leucine-rich motifs of type A and type B. “X” denotes any amino acid; “a” denotes an aliphatic amino acid. Conserved residues are shown in bold in type B. In the ribonuclease inhibitor, leucine residues 2, 5, and 7 from the  strand pack against leucine residues 17, 20, and 24 from the  helix as well as leucine residue 12 from the loop to form a hydrophobic core between the  strand and the  helix.

11. Alpha / Beta Structures Visualization using Chimera PDBfile 1fue Flavodoxin from Helicobacter pylori. Freigang, J. 2002. PDBfile 4h2d NDOR1 (NADPH-dependent diflavin oxidoreductase 1. Banci, L. 2013. PDBfile 2fcr “Crystal Structure of Oxidized Flavodoxin from a red algae Chondrus crispus refined at 1.8A resolution. Description of the flavin mononucleotide binding site.” Fukuyama, K. (1992) J. Mol. Biol. 225: 775-789. PubMed 1602481.